Research news

The patterns of variation between genomes of standard laboratory inbred mice are not
as simple as generally believed, according to a team reporting in Proceedings of the National Academy of Sciences USA. The results suggest that researchers will be forced to use other methods in quantitative
trait loci (QTL) mapping, as gene identification will become "not impossible, but
more challenging," said Richard Mott, who led the study with Jonathan Flint at the Wellcome Trust Centre for Human Genetics,
Oxford (Proc Natl Acad Sci USA 2004, 101:9734-9739).

"Inbred strains are great in the sense that they're completely homozygous," said
Mott. But laboratory mice were bred originally by amateur scientists who used anything
they could catch, said Mott. "They weren't created, generally speaking, for genetic
research. The question is, if you look at the genomes of these inbred strains in detail,
how do they differ?"

Mott and his team sequenced about 12% of a 4.8-megabase region known to contain a
QTL affecting anxiety in each of eight inbred strains, in pieces distributed fairly
uniformly to ensure a good sampling of the region at high resolution. "Essentially,
we were sampling every 10 kb," said Mott.

Mott's team investigated whether the same group of strains of inbred mice showed one
variant while the other group showed a different variant - the simplest picture of
genome variation - based on data from low-level scans of the mouse genomes.

However, instead of a picture of clear haplotype blocks - well defined boundaries
showing a shift from one pattern of differences between strains to a different pattern
- Mott's team found a structure of haplotype sharing that resembled a mosaic of ancestral
trees. Different regions showed a different phylogenetic tree relating the eight strains.
"You would see straight distributions which were consistent with the particular family
tree linking the eight strains - but that family tree would change as you went along,"
Mott said.

One of the main conclusions was that "we are going to nee - if not the full sequence
of inbred strains - we are going to need data at a very high resolution. It won't
be enough just to sample steps at every few hundred kb - which is what people are
doing at the moment," said Mott.

"It is one of the first papers to take a serious look at detailed sequence comparison
across a large number of strains, and I think the results make a great deal of sense,"
said Mark Daly, research fellow at the Whitehead Institute, "particularly since we have done a very
similar study with concordant results." That study is in press, Daly said.

The different conformations of single nucleotide polymorphisms across the eight strains
that they looked at show that 99% of the variation amongst the strains is captured
by 13 different patterns, said Daly, who was not involved in the study. "It does in
fact offer a very optimistic outlook for how much work will be required in these positional
cloning projects in mice," he said.

"I think that this is an important message, and it relies on accurate sequencing
and accurate knowledge of the true base pair sequences in the mouse. And I think it's
true that that information is not completely accurate yet," said Tamara J. Phillips, professor and vice-chair in the Department of Behavioral Neuroscience, Oregon Health
and Science University. "How likely it is that we are going to have the resources
to go at it the way that they did? That's another question."

"Perhaps the title says it is 'unexpected complexity,' but I think that's in part
because there have been some very naïve proposals and naïve interpretations of genetic
variation data," said Daly. "I think that more sophisticated readers will not find
this complexity necessarily unexpected."